tbuckley/cabot-search huggingface dataset:
Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues
Authors: Elisa Menozzi, Marco Toffoli, Anthony H.V. Schapira
Journal: Pharmacology & Therapeutics (2023)

The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation of GCase substrates. Carriers of GBA1 variants have an increased risk of developing Parkinson disease (PD), with odds ratio ranging from 2.2 to 30 according to variant severity. GBA1 variants which do not cause GD in homozygosis can also increase PD risk. Patients with PD carrying GBA1 variants show a more rapidly progressive phenotype compared to non-carriers, emphasising the need for disease modifying treatments targeting the GBA1 pathway. Several mechanisms secondary to GCase dysfunction are potentially responsible for the pathological changes leading to PD. Misfolded GCase proteins induce endoplasmic reticulum stress and subsequent unfolded protein response and impair the autophagy-lysosomal pathway. This results in α-synuclein accumulation and spread, and promotes neurodegenerative changes. Preclinical evidence also shows that products of GCase activity can promote accumulation of α-synuclein, however there is no convincing evidence of substrate accumulation in GBA1-PD brains. Altered lipid homeostasis secondary to loss of GCase activity could also contribute to PD pathology. Treatments that target the GBA1 pathway could reverse these pathological processes and halt/slow the progression of PD. These range from augmentation of GCase activity via GBA1 gene therapy, restoration of normal intracellular GCase trafficking via molecular chaperones, and substrate reduction therapy. This review discusses the pathways associated with GBA1-PD and related novel GBA1-targeted interventions for PD treatment.
Engineered macrophages acting as a trigger to induce inflammation only in tumor tissues
Authors: Kenta Tanito, Teruki Nii, Yuta Yokoyama, Haruka Oishi, Mayuka Shibata, Shoichi Hijii, Ryosuke Kaneko, Chuya Tateishi, Shoko Ito, Akihiro Kishimura, Takeshi Mori, Yoshiki Katayama
Journal: Journal of Controlled Release (2023)
Safety and effectiveness of vaccines against COVID-19 in children aged 5–11 years: a systematic review and meta-analysis
Authors: Vanessa Piechotta, Waldemar Siemens, Iris Thielemann, Markus Toews, Judith Koch, Sabine Vygen-Bonnet, Kavita Kothari, Kathrin Grummich, Cordula Braun, Philipp Kapp, Valérie Labonté, Ole Wichmann, Joerg J Meerpohl, Thomas Harder
Journal: The Lancet Child & Adolescent Health (2023)
SARS-CoV-2 incubation period across variants of concern, individual factors, and circumstances of infection in France: a case series analysis from the ComCor study
Authors: Simon Galmiche, Thomas Cortier, Tiffany Charmet, Laura Schaeffer, Olivia Chény, Cassandre von Platen, Anne Lévy, Sophie Martin, Faïza Omar, Christophe David, Alexandra Mailles, Fabrice Carrat, Simon Cauchemez, Arnaud Fontanet
Journal: The Lancet Microbe (2023)
Mental health reforms in Buenos Aires, Argentina
Authors: Alejandra Barcala, Silvia Faraone
Journal: The Lancet Psychiatry (2023)

Argentina, with a population of 40 million people, has a history of psychosocial vulnerability and social inequality,1 which has been exacerbated by the COVID-19 pandemic. In 2010, the National Mental Health Law No. 26657 was enacted. This law is a substantial step forward in protecting the rights of individuals with mental health conditions as it rejects the previous tutelary paradigm2 based on a conception of the person as an object of protection, which had prevailed until then. The law calls for the closure of all psychiatric institutions and the development of a comprehensive, community-based, territorial assistance model based on interdisciplinary and intersectoral work.
Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study
Authors: Thomas E Merchant, Mary Ellen Hoehn, Raja B Khan, Noah D Sabin, Paul Klimo, Frederick A Boop, Shengjie Wu, Yimei Li, Elizabeth A Burghen, Niki Jurbergs, Eric S Sandler, Philipp R Aldana, Daniel J Indelicato, Heather M Conklin
Journal: The Lancet Oncology (2023)
Eosinophil Subtypes in Adults with Asthma and Adults with Chronic Obstructive Pulmonary Disease
Authors: Carlos Cabrera López, Alejandra Sánchez Santos, Angelina Lemes Castellano, Sara Cazorla Rivero, Joaquín Breña Atienza, Enrique González Dávila, Bartolomé Celli, Ciro Casanova Macario
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: There is a differential response to eosinophilic modulation between patients with asthma and those with chronic obstructive pulmonary disease (COPD). There is also evidence of different subtypes of eosinophils in murine models. However, no study has compared eosinophil subtypes in individuals with COPD and in those with asthma. Objectives: Study the differences in eosinophils subtypes based in the surface protein expression in COPD patients and asthmatic patients. Methods: We studied 10 stable subjects in each of four groups: subjects with COPD, subjects with asthma, smokers without COPD, and healthy volunteers. Subjects with COPD and those with asthma were matched by age, sex, and FEV1% predicted. The following variables were determined: anthropometrics, smoking, exacerbation history, medication use, lung function, and comorbidities. Using flow cytometry and confocal microscopy from blood samples, we determined differences in eosinophil surface proteins and classified them as 1) resident eosinophils (Siglec-8+CD62L+IL-3Rlo) or 2) inflammatory eosinophils (iEos; Siglec-8+CD62LloIL-3Rhi). IL-5 receptor was also determined. Findings were validated in 59 patients with COPD and in 17 patients with asthma. Measurements and Main Results: Patients with asthma had a higher proportion of iEos (25 ± 15%) compared with those with COPD (0.5 ± 1%), smokers without COPD (0.14 ± 0.24%), and healthy volunteers (0.67 ± 1.72%). In patients with asthma, the proportion of iEos was independent of total eosinophil number. iEos had more IL-5 receptors than resident eosinophils (777.02 ± 124.55 vs. 598.35 ± 318.69; P < 0.01). In patients with COPD, there was no relation between iEos number and inhaled corticosteroid use, disease severity, or exacerbations rate. The findings in patients with COPD and those with asthma were confirmed in validation cohorts. Conclusions: There are differences in the subtypes of circulating eosinophils between patients with asthma and those with COPD. This could have clinical implications in the interpretation of eosinophil significance and the approach to therapy in these patients.
Financial Toxicity in Cancer Care: Implications for Clinical Care and Potential Practice Solutions
Authors: Hiba M. Khan, Scott Ramsey, Veena Shankaran
Journal: Journal of Clinical Oncology (2023)

Patients with cancer face an array of financial consequences as a result of their diagnosis and treatment, collectively referred to as financial toxicity (FT). In the past 10 years, the body of literature on this subject has grown tremendously, with a recent focus on interventions and mitigation strategies. In this review, we will briefly summarize the FT literature, focusing on the contributing factors and downstream consequences on patient outcomes. In addition, we will put FT into context with our emerging understanding of the role of social determinants of health and provide a framework for understanding FT across the cancer care continuum. We will then discuss the role of the oncology community in addressing FT and outline potential strategies that oncologists and health systems can implement to reduce this undue burden on patients with cancer and their families.
Tumor Genomic Profile Is Associated With Arterial Thromboembolism Risk in Patients With Solid Cancer
Authors: Stephanie Feldman, Dipti Gupta, Babak B. Navi, Ka-Wai Grace Ho, Peter Willeit, Sean Devlin, Kelly L. Bolton, Maria E. Arcila, Simon Mantha
Journal: JACC CardioOncology (2023)

Patients with cancer have an increased risk for arterial thromboembolism (ATE). Scant data exist about the impact of cancer-specific genomic alterations on the risk for ATE.The aim of this study was to determine whether individual solid tumor somatic genomic alterations influence the incidence of ATE.A retrospective cohort study was conducted using tumor genetic alteration data from adults with solid cancers who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets testing between 2014 and 2016. The primary outcome, ATE, was defined as myocardial infarction, coronary revascularization, ischemic stroke, peripheral arterial occlusion, or limb revascularization and identified through systematic electronic medical record assessments. Patients were followed from date of tissue-matched blood control accession to first ATE event or death, for up to 1 year. Cause-specific Cox proportional hazards regression was used to determine HRs of ATE for individual genes adjusted for pertinent clinical covariates.Among 11,871 eligible patients, 74% had metastatic disease, and there were 160 ATE events. A significantly increased risk for ATE independent of tumor type was noted for the KRAS oncogene (HR: 1.98; 95% CI: 1.34-2.94; multiplicity-adjusted P = 0.015) and the STK11 tumor suppressor gene (HR: 2.51; 95% CI: 1.44-4.38; multiplicity-adjusted P = 0.015).In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS and STK11 were associated with an increased risk for ATE independent of cancer type. Further investigation is needed to elucidate the mechanism by which these mutations contribute to ATE in this high-risk population.
Long versus short peroral endoscopic myotomy for the treatment of achalasia: results of a non-inferiority randomised controlled trial
Authors: Pietro Familiari, Federica Borrelli de Andreis, Rosario Landi, Francesca Mangiola, Ivo Boskoski, Andrea Tringali, Vincenzo Perri, Guido Costamagna
Journal: Gut (2023)

Peroral endoscopic myotomy (POEM) has become standard treatment for achalasia with comparable efficacy to surgery. In most of published series, the length of myotomy is 12-13 cm. Shorter cuts could have the advantage of shorter procedure time and possibly reduced gastro-oesophageal reflux disease (GORD) rate.
Long-term, in vivo therapeutic effects of a single dose of miR-145 micelles for atherosclerosis
Authors: Deborah D. Chin, Neil Patel, Woori Lee, Sonali Kanaya, Jackson Cook, Eun Ji Chung
Journal: Bioactive Materials (2023)

Atherosclerosis is a chronic inflammatory disease that is characterized by the build-up of lipid-rich plaques in the arterial walls. The standard treatment for patients with atherosclerosis is statin therapy aimed to lower serum lipid levels. Despite its widespread use, many patients taking statins continue to experience acute events. Thus, to develop improved and alternative therapies, we previously reported on microRNA-145 (miR-145 micelles) and its ability to inhibit atherosclerosis by targeting vascular smooth muscle cells (VSMCs). Importantly, one dose of miR-145 micelles significantly abrogated disease progression when evaluated two weeks post-administration. Thus, in this study, to evaluate how long the sustained effects of miR-145 micelles can be maintained and towards identifying a dosing regimen that is practical for patients with chronic disease, the therapeutic effects of a single dose of miR-145 micelles were evaluated for up to two months in vivo. After one and two months post-treatment, miR-145 micelles were found to reduce plaque size and overall lesion area compared to all other controls including statins without causing adverse effects. Furthermore, a single dose of miR-145 micelle treatment inhibited VSMC transdifferentiation into pathogenic macrophage-like and osteogenic cells in plaques. Together, our data shows the long-term efficacy and sustained effects of miR-145 micelles that is amenable using a dosing frequency relevant to chronic disease patients.
Going below and beyond the surface: Microneedle structure, materials, drugs, fabrication, and applications for wound healing and tissue regeneration
Authors: Shang Lyu, Zhifei Dong, Xiaoxiao Xu, Ho-Pan Bei, Ho-Yin Yuen, Chung-Wai James Cheung, Man-Sang Wong, Yong He, Xin Zhao
Journal: Bioactive Materials (2023)

Microneedle, as a novel drug delivery system, has attracted widespread attention due to its non-invasiveness, painless and simple administration, controllable drug delivery, and diverse cargo loading capacity. Although microneedles are initially designed to penetrate stratum corneum of skin for transdermal drug delivery, they, recently, have been used to promote wound healing and regeneration of diverse tissues and organs and the results are promising. Despite there are reviews about microneedles, few of them focus on wound healing and tissue regeneration. Here, we review the recent advances of microneedles in this field. We first give an overview of microneedle system in terms of its potential cargos (e.g., small molecules, macromolecules, nucleic acids, nanoparticles, extracellular vesicle, cells), structural designs (e.g., multidrug structures, adhesive structures), material selection, and drug release mechanisms. Then we briefly summarize different microneedle fabrication methods, including their advantages and limitations. We finally summarize the recent progress of microneedle-assisted wound healing and tissue regeneration (e.g., skin, cardiac, bone, tendon, ocular, vascular, oral, hair, spinal cord, and uterine tissues). We expect that our article would serve as a guideline for readers to design their microneedle systems according to different applications, including material selection, drug selection, and structure design, for achieving better healing and regeneration efficacy.
Endoscopy Unit Level Interventions to Improve Adenoma Detection Rate: A Systematic Review and Meta-Analysis
Authors: Anshul Arora, Cassandra McDonald, Leonardo Guizzetti, Alla Iansavichene, Mayur Brahmania, Nitin Khanna, Aze Wilson, Vipul Jairath, Michael Sey
Journal: Clinical Gastroenterology and Hepatology (2023)

Adenoma detection rate (ADR) is inversely correlated with the risk of interval colon cancer and is a key target for quality improvement in endoscopy units. We conducted a systematic review and meta-analysis to identify and evaluate the effectiveness of interventions that can be implemented at the endoscopy unit level to improve ADRs.
Author Correction: Bipotent transitional liver progenitor cells contribute to liver regeneration
Authors: Wenjuan Pu, Huan Zhu, Mingjun Zhang, Monika Pikiolek, Caner Ercan, Jie Li, Xiuzhen Huang, Ximeng Han, Zhenqian Zhang, Zan Lv, Yan Li, Kuo Liu, Lingjuan He, Xiuxiu Liu, Markus H. Heim, Luigi M. Terracciano, Jan S. Tchorz, Bin Zhou
Journal: Nature Genetics (2023)

In the version of this article originally published, reference errors that arose during revisions have now been corrected as follows.In the first sentence of the Results subsection "Bipotent TLPCs differentiate into hepatocytes or BECs,"
A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer
Authors: Jinghui Liu, Yue Zhao, Daheng He, Katelyn M Jones, Shan Tang, Derek B Allison, Yanquan Zhang, Jing Chen, Qiongsi Zhang, Xinyi Wang, Chaohao Li, Chi Wang, Lang Li, Xiaoqi Liu
Journal: Cell Reports Medicine (2023)

Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.
Integration of deep learning-based histopathology and transcriptomics reveals key genes associated with fibrogenesis in patients with advanced NASH
Authors: Jake Conway, Maryam Pouryahya, Yevgeniy Gindin, David Z. Pan, Oscar M. Carrasco-Zevallos, Victoria Mountain, G. Mani Subramanian, Michael C. Montalto, Murray Resnick, Andrew H. Beck, Ryan S. Huss, Robert P. Myers, Amaro Taylor-Weiner, Ilan Wapinski, Chuhan Chung
Journal: Cell Reports Medicine (2023)

Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease globally and a leading cause for liver transplantation in the US. Its pathogenesis remains imprecisely defined. We combined two high-resolution modalities to tissue samples from NASH clinical trials, machine learning (ML)-based quantification of histological features and transcriptomics, to identify genes that are associated with disease progression and clinical events. A histopathology-driven 5-gene expression signature predicted disease progression and clinical events in patients with NASH with F3 (pre-cirrhotic) and F4 (cirrhotic) fibrosis. Notably, the Notch signaling pathway and genes implicated in liver-related diseases were enriched in this expression signature. In a validation cohort where pharmacologic intervention improved disease histology, multiple Notch signaling components were suppressed.
Meta-analysis of published cerebrospinal fluid proteomics data identifies and validates metabolic enzyme panel as Alzheimer’s disease biomarkers
Authors: Patrick W. van Zalm, Saima Ahmed, Benoit Fatou, Rudy Schreiber, Omar Barnaby, Adam Boxer, Henrik Zetterberg, Judith A. Steen, Hanno Steen
Journal: Cell Reports Medicine (2023)

To develop therapies for Alzheimer's disease, we need accurate in vivo diagnostics. Multiple proteomic studies mapping biomarker candidates in cerebrospinal fluid (CSF) resulted in little overlap. To overcome this shortcoming, we apply the rarely used concept of proteomics meta-analysis to identify an effective biomarker panel. We combine ten independent datasets for biomarker identification: seven datasets from 150 patients/controls for discovery, one dataset with 20 patients/controls for down-selection, and two datasets with 494 patients/controls for validation. The discovery results in 21 biomarker candidates and down-selection in three, to be validated in the two additional large-scale proteomics datasets with 228 diseased and 266 control samples. This resulting 3-protein biomarker panel differentiates Alzheimer's disease (AD) from controls in the two validation cohorts with areas under the receiver operating characteristic curve (AUROCs) of 0.83 and 0.87, respectively. This study highlights the value of systematically re-analyzing previously published proteomics data and the need for more stringent data deposition.
Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation
Authors: Weiyi Chen, Oliver Mehlkop, Alexandra Scharn, Hendrik Nolte, Paul Klemm, Sinika Henschke, Lukas Steuernagel, Tamara Sotelo-Hitschfeld, Ecem Kaya, Claudia Maria Wunderlich, Thomas Langer, Natalia L. Kononenko, Patrick Giavalisco, Jens Claus Brüning
Journal: Cell Metabolism (2023)

Autophagy represents a key regulator of aging and metabolism in sensing energy deprivation. We find that fasting in mice activates autophagy in the liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators, and promotes ketogenesis. AgRP neuron-dependent induction of liver autophagy relies on NPY release in the paraventricular nucleus of the hypothalamus (PVH) via presynaptic inhibition of NPY1R-expressing neurons to activate PVHCRH neurons. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and rewiring of metabolism. AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of liver autophagy in control of metabolic adaptation during nutrient deprivation.
Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis
Authors: Shozo Ohtsuki, Chenyao Wang, Ryu Watanabe, Hui Zhang, Mitsuhiro Akiyama, Melanie C. Bois, Joseph J. Maleszewski, Kenneth J. Warrington, Gerald J. Berry, Jörg J. Goronzy, Cornelia M. Weyand
Journal: Cell Reports Medicine (2023)

Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ T cells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate T cell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector T cells.
FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity
Authors: Nicolas Wieder, Juliana Coraor Fried, Choah Kim, Eriene-Heidi Sidhom, Matthew R. Brown, Jamie L. Marshall, Carlos Arevalo, Moran Dvela-Levitt, Maria Kost-Alimova, Jonas Sieber, Katlyn R. Gabriel, Julian Pacheco, Clary Clish, Hamdah Shafqat Abbasi, Shantanu Singh, Justine C. Rutter, Martine Therrien, Haejin Yoon, Zon Weng Lai, Aaron Baublis, Renuka Subramanian, Ranjan Devkota, Jonnell Small, Vedagopuram Sreekanth, Myeonghoon Han, Donghyun Lim, Anne E. Carpenter, Jason Flannick, Hilary Finucane, Marcia C. Haigis, Melina Claussnitzer, Eric Sheu, Beth Stevens, Bridget K. Wagner, Amit Choudhary, Jillian L. Shaw, Juan Lorenzo Pablo, Anna Greka
Journal: Cell Metabolism (2023)

Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches to comprehensively assess the diverse FFAs circulating in human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive. Here, we report the design and implementation of fatty acid library for comprehensive ontologies (FALCON), an unbiased, scalable, and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids associated with decreased membrane fluidity. Furthermore, we prioritized genes that reflect the combined effects of harmful FFA exposure and genetic risk for type 2 diabetes (T2D). We found that c-MAF-inducing protein (CMIP) protects cells from FFA exposure by modulating Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.